Nutritional and medicinal oral composition for veterinary use

ABSTRACT

The invention relates to a nutritional and medicinal oral composition for veterinary use, including a core of complete feed extrudate coated with at least one layer of fat. The layer of fat includes at least one medicinal agent which includes: (i) at least one preconditioned active principle in the form of a solution or a suspension of said active principle in an oily liquid, or (ii) at least one preconditioned active principle in the form of waxy granules.

This is a Continuation of application Ser. No. 14/773,141 filed Sep. 4,2015, which in turn is now allowed and is a national stage entry ofPCT/IB2014/059403 filed Mar. 3, 2014, which claims priority to FrenchPatent Application No. 13 51905 filed Mar. 4, 2013. The disclosure ofeach of the prior applications is hereby incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of oral compositions forveterinary use intended for preventing or treating disorders orpathologies in mammals, especially companion animals.

PRIOR ART

The methods for breeding farm animals and the practices for maintainingthe well-being of companion animals may require the administration ofactive pharmaceutical ingredients to these animals.

In both of these contexts relating to the maintenance of animal health,it is important that the active pharmaceutical ingredients areadministered in appropriate quality and quantity.

For farm animals, which include pigs, sheep, cattle, goats and poultry,medicinal products, notably antibiotic active principles, are generallymixed extemporaneously in the feed or in water. In fact, feed for farmanimals that is ready to use and comprises medicinal products in itscomposition is considered to represent a very small proportion of feedthat is marketed. It may be added that this medicated feed should beoffered for a variety of active principles or combinations of activeprinciples, and for a variety of combinations of nutrient elementsadapted to each species of farm animals. As a result, the costs ofmanufacture of medicated feed for farm animals would not be compatiblewith the economic constraints of the agro-food industry. In general,medicinal products intended for farm animals are in the form ofgranules, which are mixed extemporaneously with the feed, for examplewith fodder or with cereal-based pellets. However, these practices donot allow precise control of the amount of medicinal product actuallyingested by the animals, notably because the distribution of themedicated granules in the mass of fodder or in the mass of feed pelletsis not homogeneous. As an illustration, the respective individualdensities of the feed pellets and medicated granules lead to “demixing”,i.e. heterogeneous distribution of the medicated granules in the mass offeed pellets, notably because of decanting of the medicated granules inthe mixture of granules. Medicinal products may also be incorporated inthe drinking water, provided they are water-soluble and stable indissolved form.

For companion animals, in particular for dogs and cats, for which theactive pharmaceutical ingredients are administered individually ratherthan collectively, practical experience shows that there are oftendifficulties connected with poor compliance with the treatments,especially treatments by the oral route. It is known in particular thatmedicinal products presented separately in solid form, for example inthe form of pastilles, pills, soft capsules, hard capsules, and tablets,are not readily accepted by companion animals, especially dogs and cats,even when these solid forms are mixed with their food, and regardless ofthe form of the food, for example mash or pellets. Poor compliance withmedicinal treatments for companion animals is further increased when theactive principle has a pronounced taste, for example a bitter taste,owing to the highly developed sense of smell and taste of these animals.

Incorporation of a medicinal product in animal feed means that thecharacteristics of the final nutritional and medicinal composition mustmeet the requirements of the regulations governing the marketing ofhealth products. A marketing authorization will only be granted if,notably, it is established with certainty that the target dose of activeprinciple is administered to the animal accurately and reproducibly. Themethod for preparing the composition must therefore be perfectlycontrolled.

Various solutions have been proposed for supplying medicinal productsfor oral administration that are able to ensure good compliance of theanimals with treatment.

Specifically for farm animals, feed pellets coated with a cohesive gelcontaining the active principle have been proposed (see PCT applicationNo. WO 96/22028).

For companion animals, a variety of solutions has also been proposed, inparticular for reducing the problems of compliance with preventive ortherapeutic medicinal treatments, quite particularly the problems ofcompliance with medicinal treatments for dogs and cats.

For example, European patent application No. EP 1 247 456 describespharmaceutical compositions in the form of tablets in which the activeprinciple is mixed with an appetizing agent comprising one or morenatural or artificial flavors, notably brewer's yeast, the appetizingagent being intended notably to mask the taste of the active principle.A solution based on a similar principle is disclosed in PCT applicationNo. WO 03/075895, which describes tablets, notably based on brewer'syeast, in the mass of which composite particles are dispersed comprisingthe active principle of interest. The composite particles are formedfrom a core of inert support that is coated with a layer containing theactive principle, the layer of active principle itself being coveredwith an outer protective layer of a polymer material intended to maskthe taste of the active principle. In the tablets described in thisdocument, the particles of active principle are present in the tabletmass, for example the mass consisting of brewer's yeast, which has thefunction of an appetizing agent. Moreover, the technique employed inthis document requires the availability of complex and expensiveequipment.

In order to overcome the problems of compliance with therapeutictreatments in animals, PCT application No. WO 01/49272 proposes solidoral formulations of veterinary medicinal products comprising, within amolded mass containing lipids and aromatic agents, granules containingthe active principle. In these granules, the active principle ismicro-encapsulated in a polymer matrix, in particular an ethylcellulosematrix.

Food supplements in which the active principle of interest isincorporated have also been described.

We may mention PCT application No. WO 01/35925, which describesveterinary food products comprising an active pharmaceutical ingredient,and in which the taste of said active principle is masked, said activeprinciple also being protected against degradation. This documentdescribes in particular microparticles consisting of calcium alginategel, in the mass of which an active principle of interest isincorporated, said microparticles themselves being enclosed in amaterial containing powdered biscuit and flour, the mixture being madecohesive owing to the presence of a binder.

In general, the methods of manufacture of pellets for animals comprise astep of obtaining a crude extrudate core comprising a mixture ofnutrients (e.g. proteins, lipids, carbohydrates), and in a final step ofthe method, this core of extrudate is coated hot with a layer of fat oroil, generally by vapor deposition or spraying of the liquefied fat orheated oil on the surface of the crude extrudate core. After cooling,the end product is obtained, which is an extrudate treated byapplication of fat or oil (also called “treated extrudate”). In thefinal step of the method, the main functions of heating of the fat oroil are (i) liquefying the fat or oil in order to allow coating of thecrude extrudate by vapor deposition or spraying and (ii) if necessary,sterilizing the surface of the crude extrudate by heat and protectingthe surface of the crude extrudate against colonization by pathogenicmicroorganisms, such as pathogenic bacteria of the genus Salmonella.

The preparation of pellets for animals, where the core is coated with alayer of animal or vegetable fat according to the general methoddescribed above, is notably illustrated in PCT application No. WO2012/099786. According to this method, the fat composition is firstliquefied by heating, for example to a temperature of about 125° C.,then the liquid fat is sprayed onto the core of the pellets, and thenthe pellets thus treated are conveyed to a vibrating air-fluidized bedcooling device. Other methods of obtaining pellets for animalscomprising a step of hot application of an outer coating layer of fat oroil are described notably in patent application No. US 2010/0303968 andin PCT applications Nos. WO 2010/138372 and WO 2011/091111. Moreover, agreat many of the known methods comprise a final step of drying thepellets at high temperature, for example at a temperature of 140° C., asdescribed for example in the aforementioned PCT application No. WO2011/091111.

The type of method described above, comprising a final step ofhigh-temperature coating of a crude extrudate with a fat or a liquefiedoil, has also been used in the prior art for making pellets for animalscomprising, within the coating of the final coated extrudate with fat,one or more additives, called “active” additives, which may bebeneficial for the nutrition or health of the animal.

An illustration of such a method for obtaining pellets comprising anactive pharmaceutical ingredient is presented in PCT application No. WO2010/030614. This document describes the manufacture of pellets foranimals possessing a protein core (“crude extrudate”), in which theprotein core is coated with an additional layer that may contain one ormore so-called “active” additives or components, such as sugars, gums,animal or vegetable proteins, vitamins, fatty acids, or biologicalagents such as probiotic microorganisms and enzymes. This documentdescribes in particular a method of manufacturing pellets comprising acore based on vegetable proteins, which is coated with a layer of fatcomprising a probiotic microorganism. The cores based on vegetableproteins are prepared in a first step of the method. Then the corecoating composition is prepared by mixing together the probioticmicroorganisms and a fat composition. Then the cores are coated with alayer of the mixture of fat and probiotics by placing the cores in anair-type fluidized bed mixer and by supplying the air-type fluidized bedmixer with the mixture of fat and probiotics, which has been liquefiedbeforehand by heating, for example at a temperature of 56° C. After acooling step, the end product (also called “treated extrudate”) isobtained. All these techniques involve a high-temperature step in thepresence of active principles, which causes a varying degree ofdegradation of the active principle.

There is a need for oral veterinary nutritional and medicinalcompositions, alternative or improved relative to the knowncompositions, that allow stable and effective incorporation of sensitiveand/or bitter active principles and that can be manufactured at anacceptable cost for the animal feed industry.

There is also a need for improved methods for preparing oral veterinarynutritional and medicinal compositions.

SUMMARY OF THE INVENTION

The present invention provides a method for obtaining a nutritional andmedicinal oral composition for veterinary use comprising the followingsteps:

-   -   a) supplying cores of feed extrudate, and    -   b) coating the cores of complete feed extrudate supplied in        step a) with at least one layer of fat comprising at least one        medicinal agent, said medicinal agent comprising (i) at least        one preconditioned active principle in the form of a solution or        a suspension of said active principle in an oily liquid or (ii)        at least one preconditioned active principle in the form of waxy        granules, at a temperature below 40° C.

In certain embodiments of the method, step b) comprises the followingsteps:

-   -   b1) bringing the cores of complete feed extrudate supplied in        step a) into contact with at least one medicinal agent, said        medicinal agent comprising (i) at least one preconditioned        active principle in the form of a solution or of a suspension of        said active principle in an oily liquid or (ii) at least one        preconditioned active principle in the form of waxy granules,        and    -   b2) coating the extrudate cores obtained at the end of step b1)        with at least one layer of fat, at a temperature below 40° C.

In other embodiments of the method, step b) comprises the followingsteps:

-   -   b3) obtaining a fat composition comprising a medicinal agent,        said medicinal agent comprising (i) at least one preconditioned        active principle in the form of a solution or of a suspension of        said active principle in an oily liquid or (ii) at least one        preconditioned active principle in the form of waxy granules,        and    -   b4) coating the extrudate cores obtained at the end of step a)        with at least one layer of the fat composition comprising said        active principle obtained at the end of step b3), at a        temperature below 40° C.

For the purposes of the present description, the term “active principle”denotes an active pharmaceutical ingredient accepted by a person skilledin the art, i.e. a substance that is included in the composition of amedicinal product and that endows said medicinal product with itspreventive or curative therapeutic properties.

For the purposes of the present description, a preconditioned activeprinciple in dissolved form or in suspension in an oily liquid or in theform of waxy granules may also be called “medicinal agent” or “medicatedpremix”.

The coating layer of fat comprises at least one fat of animal orvegetable origin.

In certain embodiments of the method, the layer of fat is solid at atemperature below 25° C. The fat can then be worked by kneading ormixing without adding heat, to obtain a fluid texture suitable for useas a coating agent. The layer of fat may comprise at least one fatselected from hog fat, lard, suet, duck fat or fish oil.

In other embodiments, the layer of fat is liquid at a temperature of 25°C. The layer of fat may for example comprise a fish oil.

In certain embodiments of the method, the active principle(s) includedin the medicinal agent is(are) sensitive to moisture.

In certain embodiments of the method, the active principle is intendedfor preventing or treating a disorder or a chronic disease or a diseaserequiring long and repeated treatment, for example daily. Such diseasesmay be hepatic, renal, vascular, digestive, inflammatory, infectious orrespiratory-tract chronic diseases, for example renal insufficiency, orcancer. The active principle may thus be selected from metronidazole,neomycin, bronchodilators such as aminophylline, nonsteroidalanti-inflammatories such as carprofen, meloxicam, robenacoxib,mavacoxib, firocoxib, deracoxib, ciclosporin, S-adenosyl-methionine,beta-blockers, aldosterone receptor inhibitors, such as eplerenone orspironolactone, amlodipine, pimobendan, levosimendan, torasemide,furosemide, alkaloids such as theophylline, antiangiogenic agents etc.In the case of renal insufficiency in particular, said active principlemay be selected from angiotensin-converting enzyme inhibitors (ACEinhibitors), inhibitors of renin and antagonists of the angiotensin IIreceptor (compounds ending in “-sartan” such as losartan).

The angiotensin-converting enzyme inhibitors may be selected frombenazepril, enalapril, ramipril, quinapril, preindopril, lisinopril,imidapril, zofnopril, trandolapril, as well as salts thereof.

The invention supplies a nutritional and medicinal oral composition forveterinary use, which may also be called medicated feed, comprising acore of complete feed extrudate, said core being coated with at leastone layer of fat, said layer of fat comprising at least one activeprinciple in the form of particles, said active principle beingpreconditioned in dissolved form or in suspension in an oily liquid orin the form of waxy granules.

The present invention also relates to the use of a composition asdefined above, for making a nutraceutical for preventing or treating achronic disease or one requiring daily treatment, for example renalinsufficiency in a nonhuman mammal, in particular dogs and cats.

It also relates to a premix composition for making a nutritional andmedicinal composition comprising an oily suspension of particles ofnon-microencapsulated benazepril.

According to the invention, a medicated premix composition is alsosupplied, for making a nutritional and medicinal composition comprisingparticles of non-microencapsulated benazepril distributed in ahydrophobic medium comprising at least one wax, in the form of waxygranules.

DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the theoretical profiles of pharmacological effectof:

FIG. 1A: tablets of the pharmaceutical specialty Fortekor®,

FIG. 1B: oral veterinary composition described in example 1

FIGS. 1A and 1B show (i) curve of plasma concentration of benazeprilat(plasma metabolite of benazepril) obtained by modeling and materializedby the solid curves, expressed in ng/mL (ordinate on left) and (ii)curve representing the percentage ACE (angiotensin-converting enzyme)inhibition materialized by the dotted curves, expressed in percentageACE inhibition (ordinate on right).

Abscissa: time after first oral administration, expressed in hours.

FIG. 2 shows comparison of the theoretical pharmacological effects (i)of the oral veterinary composition described in example 1 (continuousline) and (ii) of the pharmaceutical specialty Fortekor® (discontinuousline) at the same dose of 600 μg/kg of benazeprilat, on plasma ACEinhibition. Ordinate: percentage ACE inhibition. Abscissa: time afterfirst oral administration, expressed in hours.

FIG. 3 illustrates the mean (±SD) maximum concentrations (Cmax) ofbenazeprilat observed on D1 and D8 after treatment with Fortekor (columnwith squares) versus the composition according to the invention (Inv)(filled column) during studies A and B. Ordinate: plasma concentrationof benazeprilat, expressed in g/L. Abscissa, from left to right: (1)Study A, Fortekor Day 1, (2) Study A, Inv Day 1, (3) Study B, FortekorDay 1, (4) Study B, Inv Day 1, (5) Study A, Fortekor Day 8, (6) Study A,Inv Day 8, (7) Study B, Fortekor Day 8, (8) Study B, Inv Day 8.

FIG. 4 illustrates the area under the curve of the plasma concentrationsof benazeprilat AUC last mean benazeprilat (±SD) on D1 and D8 aftertreatment with Fortekor versus the composition according to theinvention during studies A and B. Ordinate: Mean value of AUC Last,expressed in μg·h/L of benazepril. Abscissa, from left to right: (1)Study A, Fortekor Day 1, (2) Study A, VIRBAC Day 1, (3) Study B,Fortekor Day 1, (4) Study B, Inv Day 1, (5) Study A, Fortekor Day 8, (6)Study A, Inv Day 8, (7) Study B, Fortekor Day 8, (8) Study B, Inv Day 8.

FIG. 5 illustrates the area under the curve of the mean (±SD) plasmaconcentrations of benazeprilat (AUC last corr) on D1 and D8 aftertreatment with Fortekor versus the composition according to theinvention during studies A and B. Ordinate: Value of AUC Last corr,expressed in μg·h/L of benazepril. Abscissa, from left to right: (1)Study A, Fortekor Day 1, (2) Study A, Inv. Abscissa, from left to right:(1) Study A, Fortekor Day 1, (2) Study A, Inv Day 1, (3) Study B,Fortekor Day 1, (4) Study B, Inv Day 1, (5) Study A, Fortekor Day 8, (6)Study A, Inv Day 8, (7) Study B, Fortekor Day 8, (8) Study B, Inv Day 8.

FIG. 6 illustrates a comparison of the pharmacokinetic profiles ofbenazeprilat after administration of the composition Inv (squares) andof the composition Fortekor (crosses) respectively. Ordinate: plasmaconcentration of benazeprilat, expressed in ng/ml. Abscissa, comparisonof the pharmacokinetic profiles of the composition Fortekor (uppercurves with a narrow peak) and of the composition Inv (lower curves witha broad peak), respectively at Time 0, at Time 45 hours and at Time 175hours. It can be seen that the Cmax of Inv is lower than the Cmax withFortekor; nevertheless FIGS. 4 and 5 show that the AUCs are comparable,thus giving Inv a better pharmacological profile in toxicological terms,with comparable or even greater efficacy.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method for preparing a nutritional andmedicinal oral composition, for veterinary use.

The present invention also provides novel oral veterinary compositionsthat are both nutritional and medicinal.

The applicant became aware that there was a need for compositionsintended for animals that include both (i) the constituents necessaryfor complete nutrition of these animals and (ii) one or more activeprinciples intended to prevent or treat disorders or pathologies thatcould affect, or that do affect, said animals.

The applicant therefore undertook to develop compositions for veterinaryuse for oral administration comprising nutrient elements present in asuitable quality and quantity for complete nutrition of the animals,said compositions also including at least one active principle that ispresent in suitable quality or quantity for preventing or treating adisorder or a disease in said animals.

To achieve this objective, the applicant undertook to identify solutionsthat allow the coexistence, within one and the same oral composition, ofthe substances necessary for constituting a complete food, in particularsubstances containing lipids, proteins or carbohydrates, and at leastone active principle, and in which, notably:

-   -   the active principle remains stable for a long period,    -   the presence of the active principle in the composition does not        affect the animals' appetite for this composition,    -   the formulation selected allows effective masking of the taste        of the active principle when this active principle has an        unpleasant taste,    -   the active principle is distributed homogeneously in the        composition, both in each dosage unit and from one dosage unit        to another,    -   the active principle is released in appropriate quality and        quantity for obtaining the preventive or curative pharmaceutical        effect required, notably owing to the fact that it is included        in a nutritional composition that has a long residence time in        the stomach,    -   the specific characteristics of the composition do not require        the use of a complex and/or expensive method of preparation;        said composition can be prepared using an industrial        manufacturing chain of a known type    -   the method employed does not have an adverse effect on the        stability of the active principle and its content.

After considerable research, the applicant developed a method forpreparing nutritional and medicinal oral compositions that is simple toimplement and that makes it possible to manufacture compositions havingthe advantageous properties specified above.

The present invention relates to a method for obtaining a nutritionaland medicinal oral composition for veterinary use comprising thefollowing steps:

-   -   a) supplying cores of complete feed extrudate, and    -   b) coating the cores of complete feed extrudate supplied in        step a) with at least one layer of fat comprising at least one        medicinal agent, said medicinal agent comprising (i) at least        one preconditioned active principle in the form of a solution or        of a suspension of said active principle in an oily liquid        or (ii) at least one preconditioned active principle in the form        of waxy granules, at a temperature below 40° C.

The extrudate cores that are supplied in step a) include (i) theextrudate cores comprising a mixture of nutritional substances that havenot undergone a final treatment step by surface application of fat orliquefied oil at a high temperature, i.e. in a “hot” process, said coresare also called “crude extrudate cores”, and (ii) the extrudate coresprepared according to a method comprising a step of surface applicationof fat or hot liquefied oil, said cores are also called “treatedextrudate cores”, for the purposes of the present description.

Surprisingly, the applicant has shown that the “cold” incorporation of amedicinal agent as defined in the present description in a fat or oilcomposition forming a coating layer of a core of complete feed extrudateimparts great stability over time to the active principle that iscontained in said medicinal agent, i.e. both (i) protection of theactive principle against degradation by the external environment and(ii) protection of the active principle against degradation caused bycontact of the latter with the substances contained in the extrudatecore. It will be understood that this characteristic makes it possibleto prevent, or at least substantially reduce, degradation of activeprinciples that are sensitive to hydrolysis.

In particular, the fact that the medicinal agent is incorporated “cold”in the coating layer of fat or oil, without a step of liquefaction byheating, preserves the active principle contained in said medicinalagent against any effect of degradation by heat.

Moreover, the applicant has shown that “cold” incorporation of themedicinal agent in the coating layer of fat or oil prevents, or at thevery least substantially reduces, penetration of the fat or oilcontained in the coating layer into the bulk of the extrudate core. Thisspecific characteristic prevents any degradation of some or all of theactive principle contained in the medicinal agent owing to contact ofthe latter with the extrudate core. This characteristic also makes itpossible, owing to the presence of all or almost all of the medicinalagent in the coating layer, to control the profile of release of theactive principle, with the aim of obtaining an optimal pharmacologicaleffect.

It is thus shown that the particular combination of characteristics ofthe oral veterinary composition above allows optimal release of theactive principle(s) of interest, so as to induce an optimal preventiveor therapeutic medicinal effect. In particular, it is shown that with anoral veterinary composition as defined above, administered as a food, aprofile of release of the active principle is obtained which is of theslow or prolonged release type, which allows effective plasmaconcentrations of said active principle to be maintained for a longertime than with a medicinal product with immediate release and thusallows increased overall activity of said active principle on the targetsites of the latter in the animal's body. This means that with an oralveterinary composition according to the invention, a given preventive orcurative pharmaceutical effect can be obtained with a smaller amount ofactive principle(s) than with conventional compositions (AUC equivalentto and Cmax lower than the reference treatment).

It has also been shown according to the invention that the nutritionaland medicinal oral composition that is obtained at the end of the abovemethod has excellent properties of palatability for animals, even whenthe active principle is bitter or repellent for the animal.

It is particularly important that the feedstuff has excellentpalatability. In fact, it is recognized that cats are very sensitive tothe taste of their feed and this effect is more pronounced when a cat isill. A side effect resulting from the disease, notably renal, in cats,is loss of appetite. It is therefore crucial to be able to treat a sickcat effectively before it refuses to eat altogether. Moreover, for dailytreatment, it is very important to ensure very good palatability; infact it is necessary to avoid the animal associating the medicated feedwith an unpleasant taste, which makes compliance disastrous within a fewdays.

“Core of complete feed extrudate” means, according to the invention, thecentral part of the oral composition that consists of a mixture ofnutritional elements, notably lipids, proteins and carbohydrates, inquality and in quantity suitable for feeding the animals for which theoral composition is intended. In other words, an oral veterinarycomposition according to the invention contains the nutrient elementsessential for the animals for which it is intended.

The central part or core is in the form of a product obtained byextrusion of a nutritional raw material or of a mixture of nutritionalraw materials, for example a mixture (i) of raw materials derived fromcereals, (ii) of raw materials derived from meat, egg or fish and (iii)of fats of animal or vegetable origin. The use of an extrudate isentirely conventional in the food industry, in particular for makingfeed pellets intended for animals, in particular for companion animalssuch as dogs and cats.

As already stated above, an extrudate core comprises a crude extrudatecore and a treated extrudate core, the treated extrudate core havingbeen obtained by a method comprising a step of application, generally byvapor deposition or spraying, at high temperature, of a fat or oilcomposition which has been liquefied beforehand by heating.

For the purposes of the present description, the term “active principle”denotes an active pharmaceutical ingredient accepted by a person skilledin the art, i.e. a substance that is included in the composition of amedicinal product and that endows said medicinal product with itspreventive or curative therapeutic properties.

For the purposes of the present description, an active principle (i)preconditioned in the form of a solution or of a suspension of saidactive principle in an oily liquid or (ii) preconditioned in the form ofwaxy granules may also be called “medicinal agent” or “medicatedpremix”. A medicinal agent according to the invention may comprise asingle active principle or else a plurality of active principles, forexample 2, 3 or 4 separate active principles.

In certain embodiments of a medicinal agent comprising a plurality ofpreconditioned active principles in an oily liquid, all the activeprinciples may be dissolved in the oily liquid.

In other embodiments of a medicinal agent comprising a plurality ofpreconditioned active principles in an oily liquid, all the activeprinciples may be suspended in the oily liquid.

In yet other embodiments of a medicinal agent comprising a plurality ofpreconditioned active principles in an oily liquid, at least one of theactive principles is dissolved in the oily liquid and at least one otherof the active principles is in suspension in said oily liquid.

Thus, in the present description, the term “medicinal agent” denotes thephysical form in which the active principle is incorporated, i.e. either(i) in the form of a solution of said active principle in an oily liquidor in the form of an oily suspension of said active principle, or (ii)in the form of waxy granules, in which said active pharmaceuticalingredient is included in a powder of a hydrophobic wax.

According to the invention, an active principle may be preconditioned byincorporating said active principle in a hydrophobic wax, i.e. mainly byincorporating an active principle in the form of particles of activeprinciple included in a hydrophobic wax at a temperature between 15° C.and 25° C., for example in the form of waxy granules. The preconditionedactive principle in the form of waxy granules is advantageously in theform of a powder of particles of hydrophobic wax in which the activeprinciple is distributed. Preferably, the preconditioned activeprinciple in the form of waxy granules is in the form of a powder ofparticles of hydrophobic wax in which particles of the active principleare distributed.

Method of Obtaining an Oral Veterinary Nutritional and MedicinalComposition

In step a), as has already been stated above, the cores of complete feedextrudate are advantageously prepared by conventional techniques, forexample techniques of preparation of raw materials, mixing thereof, thenextrusion, especially extrusion/cooking, of the mixtures obtained, whichare commonly used in the area of the manufacture of pellets for animals,in particular for companion animals, including dogs or cats.

In certain embodiments of the method, the extrudate cores consist ofcores of “treated extrudate”, which are prepared by a method comprisinga step of treatment of a crude extrudate as described above byapplication of a fat or an oil liquefied beforehand by heating, asdescribed for example in PCT application No. WO 2012/099786 or in patentapplication No. US 2010/0303968 and in PCT applications Nos. WO2010/138372 and WO 2011/091111.

For preparing the extrudate cores, raw materials may be used that areeasily accessible commercially.

In certain embodiments of the method, step b) comprises the followingsteps:

-   -   b1) bringing the cores of complete feed extrudate into contact        with at least one medicinal agent, said medicinal agent        comprising (i) at least one preconditioned active principle in        the form of a solution or of a suspension of said active        principle in an oily liquid or (ii) at least one preconditioned        active principle in the form of waxy granules, and    -   b2) coating the extrudate cores obtained at the end of step b1)        with at least one layer of fat, at a temperature below 40° C.

In these embodiments of the method, the extrudate cores are brought intocontact with the medicinal agent prior to the step of coating with thelayer of fat. In these embodiments, the medicinal agent subsequentlypenetrates into the coating layer of fat, within which, notably, theactive principle is protected from degradation through contact with theexternal environment.

Step b1) may be carried out by mixing the medicinal agent with theextrudate cores, prior to the step of coating with the layer of fat.Preferably, step b1) is carried out at a temperature below 40° C.

In other embodiments of the method, step b) comprises the followingsteps:

-   -   b3) obtaining a fat composition comprising at least one        medicinal agent, said medicinal agent comprising (i) at least        one preconditioned active principle in the form of a solution or        of a suspension of said active principle in an oily liquid        or (ii) at least one preconditioned active principle in the form        of waxy granules, and    -   b4) coating the extrudate cores obtained at the end of step a)        with at least one layer of the fat composition comprising said        medicinal agent, obtained at the end of step b3), at a        temperature below 40° C.

In step b4), the extrudate cores are preferably coated by kneading ormixing the cores of extrudate, crude extrudate or treated extrudate,with a layer of fat comprising the medicinal agent that comprises theactive principle(s) of interest. Preferably, a medicinal agent is usedthat comprises an active pharmaceutical ingredient that is either (i) inthe form of a solution or of an oily suspension of the activeprinciple(s), or (ii) in the form of preconditioning of the activeprinciple(s) in a hydrophobic medium, preferably a wax, i.e. in the formof waxy granules.

Regardless of the embodiment of the method that is employed, step b),notably step b) comprising steps b1) and b2 or step b) comprising stepsb3) and b4), is preferably carried out at a temperature below 40° C.,better still below 35° C., preferably below 30° C., and especiallypreferably below 25° C. At these temperatures of carrying out step b),no degradation of the active principle(s) or of the other constituentsof the oral veterinary composition is observed. Notably, degradation ofthe proteins contained in the core of complete feed extrudate anddegradation of the vitamins are avoided, and oxidation of the fats isalso avoided.

According to a preferred embodiment, the whole of the method accordingto the invention is carried out at a temperature as stated above, namelybelow 40° C.

In general, the fat composition used for coating step b) comprises atleast one fat of animal or vegetable origin.

As has already been stated and as will be described in more detail lateron in the present description, the active principle may bepreconditioned in liquid form; either the active principle is dissolvedin the liquid, or the active principle is suspended in the liquid.

In other embodiments of the medicinal agent, the active principle is inthe form of particles and is preconditioned by incorporation in ahydrophobic wax, i.e. in the form of waxy granules.

The active principle(s) constituting the medicinal agent used in step b)of the method is(are) defined elsewhere in the present description.

The Coating Fat Composition

Various lipid substance(s) may be contained in a coating layer of fat ofthe oral veterinary composition, in particular including lipidsubstances of natural origin, in particular fats of animal or vegetableorigin.

According to certain variants of the method, the layer of fat comprisesat least one fat selected from hog fat, lard, suet, duck fat or fishoil.

Notably, the fat may be of various origins. The fat may be selected frombeef tallow, poultry fat, soybean oil, canola oil, sunflower oil, fishoil, lard, or white fat.

The lipid substances may notably be selected from:

-   -   (i) the following lipid substances of natural origin: beeswax,        lanolin, hog fat, lard, suet or fish fat, fish oil, carnauba        wax, soybean oil, peanut oil, colza oil, paraffin,        microcrystalline wax, petroleum jelly, and a mineral oil, and    -   (ii) the following lipid substances of synthetic origin: fatty        alcohol, fatty acid, ester of alcohol and fatty acid (white        wax), polyethoxylated vegetable oil, hydrogenated vegetable oil,        mono-, di- and triglycerides of fatty acids.

In a preferred variant of the invention, the lipid substance of naturalorigin is a mineral oil. In another preferred variant of the invention,the lipid substance of synthetic origin is an alcohol or a fatty acid ora mixture thereof.

Advantageously, most of the lipid substances contained in the coatinglayer of fat of an oral veterinary composition according to theinvention have a melting point above 30° C., preferably above 40° C.,and are therefore in solid form at the usual storage temperatures offood products or pharmaceuticals.

Preferably, the coating layer of fat is in the form of a paste that caneasily be worked at a temperature well below its melting point. The fatpaste is preferably obtained by kneading, or creaming, the lipidsubstance or the combination of lipid substances constituting thecoating fat.

In certain embodiments, the core of complete feed extrudate is coatedwith a plurality of layers of fat, with at least one coating layer offat comprising at least one medicinal agent.

In general, the number of coating layers of fat varies from 1 to 5. Mostoften, an oral veterinary composition according to the inventioncomprises a single coating layer of fat, which comprises at least oneactive pharmaceutical ingredient.

In these embodiments, the coating layer of fat comprising the medicinalagent(s) consists of the outer layer of the composition, said outerlayer being in contact with the external environment.

In the above embodiments, the coating layer of fat comprising at leastone medicinal agent may consist of animal fat, for example poultry fat,typically duck fat or goose fat, or else lard.

Medicinal Agent

In certain embodiments of an oral veterinary composition according tothe invention, the active principle(s) of interest comprised in themedicinal agent is(are) in dissolved form in an oily solution, or elsein the form of a suspension in an oily liquid, notably depending on thesolubility characteristics of said active principle(s).

Oily solution or oily liquid means a hydrophobic solution comprising anoil or a mixture of oils. An oil may be of natural or synthetic origin,in particular an animal, vegetable or mineral oil.

In the embodiments in which the active principle is suspended in an oilyliquid, said oily liquid may comprise, besides the oily vehicle itself,also one or more substances selected from viscosity adjusters,resuspending agents, antioxidants, preservatives, pigments, flavoringsand perfumes.

The viscosity adjusters may be selected from silica, aluminum mono-, di-and tristearate and hydrogenated castor oil.

The resuspending agents may be selected from the amphiphilicsurfactants, which include the fatty acids or the lecithins.

The antioxidants may be selected from BHA, BHT, propyl gallate or elsevitamin E, or a mixture of these excipients.

In certain advantageous embodiments of a medicinal agent according tothe invention, the active principle is in the form of particles.

In these embodiments, the active principle of the medicinal agent may bean oily suspension of the particles of active principle or else themedicinal agent may be in the form of waxy granules, in which theparticles of active principle are distributed.

In these embodiments, the active principle(s) of interest in the form ofparticles is(are) preferably in the form of microparticles.

Advantageously, the average size of the microparticles of activeprinciple is less than 400 μm, or 100 μm, and better still less than 80μm. The average size of the particles of active principle variesadvantageously from 10 μm to 50 μm, and is preferably in the range from15 μm to 35 μm. To measure the average particle size of active principlefor the purposes of the present description, preferably the laserdiffraction technique is used (“Low Angle Laser Light Scattering” orLALLS) according to the European Pharmacopeia and notably according toPh. Eur. 2.9.31: Analysis of particle size by diffraction of laser light(standard ISO 13320: 2009 & 9276.1), according to Ph. Eur. 2.9.35Fineness of powders, but also according to the method of analyticalsieving (Ph. Eur. 2.9.38; ISO 3310.1), classification according to Ph.Eur. 2.9.12.

It is to be noted that the particles of active pharmaceutical ingredientquite preferably contain only said active principle, to the exclusion ofany other compound. These non-encapsulated particles of active principletherefore do not have a layer of a material preventing contact of theactive principle(s) with the external environment, and in particular donot have a protective layer intended to preserve the active principleagainst destructive effects of the external environment. The particlesof active principle in particular do not have a layer for masking theodor or taste of the active principle.

It is shown, surprisingly, that the particulate, preferablymicro-particulate, character of the active principle, combined withabsence of a protective outer layer of the particles or microparticles(non-encapsulation), allows good adhesion and good maintenance of theactive principle in the hydrophobic layer that is not in contact withthe core of complete feed extrudate.

The inventors showed that specific advantages are obtained when theparticulate active principle is included in said coating layer of fat inthe form of a medicinal agent, i.e. after preconditioning in a lipidsubstance, and more specifically when the active principle ispreconditioned in dissolved form in an oily liquid or in the form of anoily suspension or in the form of waxy granules.

The use of the active principle in the form of preconditioning in theform of a medicinal agent as defined in the present description (i)allows great stability of the active principle in the oral veterinarycomposition and (ii) endows the oral veterinary composition withproperties of palatability leading to better compliance of ingestion ofthe oral veterinary composition by the animals. Moreover, in practicalterms, it is easier for the operator to incorporate the medicinal agentin the extrudate cores, compared with incorporation of one or moreactive principles that are not preconditioned in the form of a medicinalagent.

Thus, in certain embodiments of an oral veterinary composition accordingto the invention, the medicinal agent comprises the particulate activeprinciple(s) that is (are) preconditioned in the form of an oilysuspension.

Moreover, in certain other embodiments of an oral veterinary compositionaccording to the invention, the medicinal agent comprises the activeprinciple(s) that is (are) preconditioned in the form of waxy granules,in which the particles of active principle(s) are incorporated.

Active Principles

Owing to the fact that the oral veterinary compositions of the inventioncomprise both (i) at least one medicinal agent and (ii) nutrients inappropriate quality and quantity for complete nutrition of the animals,said oral veterinary compositions are suitable for use for preventing ortreating diseases, in particular for treating chronic diseases, whichrequires daily administration of active principle(s) over a long periodof time, for example for several months or several years, or eventhroughout the animal's life.

The chronic diseases that can be prevented or treated with an oralveterinary composition according to the invention include hepatic,renal, vascular, digestive, inflammatory, infectious orrespiratory-tract chronic diseases.

An oral veterinary composition according to the invention isspecifically advantageous when prevention or treatment of a diseaserequires both (i) administration of one or more active pharmaceuticalingredient(s) and (ii) application of a suitable diet.

An oral veterinary composition as defined in the present description maynotably be used for treating renal insufficiency.

The active principles that may be used in a medicinal agent constitutingan oral veterinary composition of the invention include metronidazole,neomycin, bronchodilators such as aminophylline, nonsteroidalanti-inflammatory drugs such as carprofen, meloxicam, robenacoxib,mavacoxib, firocoxib, deracoxib, ciclosporin, S-adenosyl-methionine,beta-blockers, aldosterone receptor inhibitors, such as eplerenone orspironolactone, amlodipine, pimobendan, levosimendan, torasemide,furosemide, alkaloids such as theophylline, antiangiogenic agents, etc.

In the case of renal insufficiency in particular, said active principlemay be selected from the angiotensin-converting enzyme inhibitors (ACEinhibitors), renin inhibitors and angiotensin II receptor antagonists(compounds ending in “-sartan” such as losartan), theangiotensin-converting enzyme inhibitors (ACE inhibitors), renininhibitors and angiotensin II receptor antagonists.

The angiotensin-converting enzyme inhibitors that may be used in an oralveterinary composition of the invention include benazepril, enalapril,ramipril, quinapril, preindopril, lisinopril, imidapril, zofnopril,trandolapril, as well as salts thereof.

The renin inhibitors that may be used in an oral veterinary compositionof the invention include pepstatin, the peptide analogs of pepstatinsuch as H-142, the peptide mimetics of pepstatin such as remikiren andthe non-peptide mimetics of pepstatin such as aliskiren, as well assalts thereof.

The angiotensin II receptor antagonists that may be used in an oralveterinary composition of the invention include valsartan, telmisartan,losartan, irbesartan, azilsartan and omesartan, as well as saltsthereof.

The active principles that may be used in a medicinal agent constitutingan oral veterinary composition of the invention also include firocoxib,ciclosporin, S-adenosyl-methionine, eplerenone, spironolactone,amlodipine and levosimendan. As stated above, an oral veterinarycomposition according to the invention may comprise, as activepharmaceutical ingredient, benazepril or a salt thereof. An oralveterinary composition of this kind is useful in the prevention ortreatment of renal insufficiency.

According to certain embodiments, an oral veterinary composition of theinvention useful for animals that are affected, or likely to beaffected, by renal insufficiency comprises (i) benazepril and (ii) acore of complete feed extrudate whose qualitative and quantitativeconstitution of nutrients is suitable for maintaining renal function inthe case of chronic renal insufficiency, for example a core of completefeed extrudate having a low phosphorus content as well as a low contentof proteins, said proteins being of high quality.

Advantageously, benazepril is used in the form of benazeprilhydrochloride.

Advantageously, benazepril or a salt thereof is present in an amountvarying from 0.0025 to 0.0100% (25 to 100 ppm) by weight, relative tothe total weight of the oral veterinary composition. For example, anoral veterinary composition according to the invention may compriseabout 50 ppm by weight of benazepril or of a salt thereof, relative tothe total weight of said oral veterinary composition.

Core of Complete Feed Extrudate

The term “extrudate” is used in the present description in itsconventional sense known by a person skilled in the art. The completefeed extrudate is the end product of a method comprising a step duringwhich a suitable mixture of nutrients is passed through the die of anextruder.

In general, a person skilled in the art can easily determine theappropriate qualitative and quantitative constitution of nutrients ofthe core of complete feed extrudate contained in an oral veterinarycomposition according to the invention, based on his general knowledgein the area of the preparation of feedstuffs for animals, including inthe area of feedstuffs for companion animals such as dogs and cats,which includes feedstuffs in the form of pellets.

In general, said extrudate core comprises nutrients in appropriatequality and quantity, for example in quality and quantity definedaccording to the regulatory standards, including the standards of thegovernment health authorities, such as the Direction Générale del'Alimentation (General Food Directorate) attached to the FrenchMinistry of Agriculture, the European Food Safety Authority (EFSA), theCenter for Veterinarian Medicine attached to the Food and DrugAdministration of the United States, or the “American Feed ControlOfficials Incorporated” of the United States.

The constituents used for preparing the extrudate core of an oralveterinary composition according to the invention include, but are notlimited to, farinaceous substances, proteinaceous substances, and fats,in the form of mixtures. In certain embodiments, the extrudate core maycomprise proteins, substances containing starch, substances containingfibers, fats, mineral substances, vitamins, in the form of mixtures orcombinations of at least two of these constituents.

The protein substances include meat, and meat derivatives, chicken, lambor mutton, turkey, beef, goat meat and fish. Meat derivatives includelungs, kidneys, livers, stomachs and intestines.

Substances containing starch include substances derived from cereals,especially substances derived from maize, wheat, rice, oats, or sorghum.

Substances containing fibers include fructooligosaccharides, beet pulp,the mannan-oligosaccharides, oat fiber, pulp of citrus fruits,carboxymethylcellulose, as well as gums such as gum arabic, guar gum, orapple or tomato pomaces, and mixtures or combinations thereof.

Fats include fats of animal origin and fats of vegetable origin.

Fats of animal origin include those that are derived from chicken,turkey, pork, beef, or from fish, as well as mixtures or combinationsthereof.

Fats of animal origin include fish oils. Fats of vegetable origininclude vegetable oils such as maize oils, soybean oils, cotton oils,palm oils, coconut oils, as well as mixtures and combinations thereof.

Mineral substances include sodium selenite, monosodium phosphate,calcium carbonate, potassium chloride, ferrous sulfate, zinc oxide,manganese sulfate, copper sulfate, manganese oxide, potassium iodide,cobalt carbonate, as well as mixtures and combinations thereof.

The vitamins include choline chloride, vitamin E, ascorbic acid, vitaminA acetate, calcium pantothenate, pantothenic acid, biotin, thiaminemonoitrate, vitamin B12, niacin, riboflavin, inositol, pyridoxinehydrochloride, vitamin D3, folic acid, vitamin C, as well as mixturesand combinations thereof.

The core of complete feed extrudate may also comprise amino acids suchas methionine, leucine, lysine, tryptophan, arginine, cysteine, asparticacid, taurine, as well as mixtures and combinations thereof.

The core of complete feed extrudate may comprise additional substancessuch as antioxidants, stabilizers, binders, thickeners, tasteexhausters, flavorings, preservatives, fillers, emulsifiers, sweeteners,buffering agents, dyes, gelling agents and humectants.

The emulsifiers and/or gelling agents include gelatin, cellulose ethers,starch, starch esters, starch ethers and modified starches. Starchincludes ungelatinized starch, fully gelatinized starch and partiallygelatinized starch, and mixtures or combinations thereof. Partially orfully gelatinized starch may be in the form of pregelatinized starch,which is hydrated at the moment of use.

Notably, the core of complete feed extrudate may comprise additionalsubstances such as carotenoids, polyphenols, fatty acids, probiotics, orprebiotics.

In certain embodiments of an oral veterinary composition according tothe invention, the quality and quantity of nutritional substances areadapted to the specific physiology of the animals with renalinsufficiency, especially cats with renal insufficiency.

In these embodiments, said extrudate core comprises lipids,carbohydrates and proteins and has a reduced phosphorus content and areduced protein content, relative to the commonly accepted normalvalues.

In certain embodiments, known cores of complete feed extrudate may beused, whose qualitative and quantitative composition of ingredients issuitable for a diet intended for animals, especially cats, with chronicrenal insufficiency. It is possible for example to use extrudate coresthat are described in PCT application No. WO 2007/084986.

In these embodiments, said extrudate core may for example comprise (i) 5to 50 wt % of proteins, (ii) from 0.001 to 1 wt % of sodium, and (iii)from 0.01 to 1 wt % of potassium, the percentages by weight beingexpressed relative to the total weight of said extrudate core. In theseembodiments, said extrudate core may for example comprise (i) 8 to 25 wt% of proteins, (ii) from 0.05 to 0.6 wt % of sodium, and (iii) from 0.05to 0.9 wt % of potassium, the percentages by weight being expressedrelative to the total weight of said extrudate core. In theseembodiments, said extrudate core may for example comprise (i) 10 to 16wt % of proteins, (ii) from 0.1 to 0.5 wt % of sodium, and (iii) from0.1 to 0.5 wt % of potassium, the percentages by weight being expressedrelative to the total weight of said extrudate core. In theseembodiments, said extrudate core may for example comprise (i) 5 to 30 wt% of proteins, (ii) from 0.01 to 2 wt % of sodium, (iii) from 0.01 to 2wt % of potassium, and (iv) from 0.2 to 1 wt % of phosphorus, thepercentages by weight being expressed relative to the total weight ofsaid extrudate core. In these embodiments, said extrudate core may forexample comprise (i) 25 to 50 wt % of proteins, (ii) from 0.1 to 2 wt %of sodium, (iii) from 0.1 to 2 wt % of potassium, and (iv) from 0.2 to 1wt % of phosphorus, the percentages by weight being expressed relativeto the total weight of said extrudate core.

In one variant, the invention is more specifically suitable for treatingor preventing renal insufficiency. In this case, the core of completefeed extrudate comprises an amount of starch of at most 25 wt %, forexample an amount of starch in the range from 20 to 25 wt %, for examplean amount of starch in the range from 10 to 15 wt %, relative to thetotal weight of said extrudate core. Advantageously, the core ofcomplete feed extrudate comprises phosphorus and sodium in suitableamounts.

Advantageously, said extrudate core comprises essentially, or comprisesexclusively, proteins of animal origin.

Advantageously, said extrudate core also comprises vitamins, and inparticular one or more of the following vitamins: vitamin A, vitamin D,vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B6,biotin, folic acid and vitamin B12.

Advantageously, said extrudate core comprises one or more traceelement(s). In particular, said extrudate core may comprise one or moreadditional elements selected from copper, iron, iodine, manganese,magnesium, selenium and zinc.

Other Characteristics of the Oral Veterinary Composition

Advantageously, the extrudate core of an oral veterinary compositionaccording to the invention represents from 75 to 95 wt %, relative tothe total weight of said composition.

Advantageously, the total of the layers of fat coating said extrudatecore represents from 5 to 25 wt %, relative to the total weight of saidcomposition, it being understood that the weight of the medicinalagent(s) contained in at least one of the layers of fat is negligiblerelative to the total weight of the oral veterinary composition.

The coating layer of fat comprising the medicinal agent(s) must bepresent in a sufficient amount for protecting the active principle(s)contained in said medicinal agent(s) against contact with the externalenvironment, and in particular against contact with water that may bepresent in the external environment, including in the form of waterpresent in a humid atmosphere.

In certain embodiments of the oral veterinary composition of theinvention, the coating layer of fat comprising the active principle(s)represents from 4 to 15 wt %, relative to the total weight of saidcomposition. In these embodiments, the oral veterinary compositioncomprises a plurality of layers of fat, the layer(s) of fat other thanthe coating layer comprising the medicinal agent advantageouslyrepresenting from 1 to 10 wt %, relative to the total weight of saidoral veterinary composition.

In advantageous embodiments, an oral veterinary composition according tothe invention, the coating layer of fat containing the activeprinciple(s) represents from 0.5 to 15 wt %, the percentages by weightbeing expressed relative to the total weight of said oral veterinarycomposition. In these embodiments, the oral veterinary compositioncomprises a plurality of layers of fat, the layer(s) of fat other thanthe coating layer comprising the medicinal agent advantageouslyrepresenting from 4 to 10 wt %, relative to the total weight of saidoral veterinary composition.

In the embodiments of the oral veterinary composition of the inventionin which the medicinal agent comprises at least one active principle inthe form of an oily suspension of the latter, at least a proportion, ifnot all, of the oil contained in the oily suspension of initial activeprinciple is present in the coating layer of fat comprising said activeprinciple. In these specific embodiments, the layer of fat comprisingthe active principle may comprise from 0.05 to 2 wt % of the oil derivedfrom the oily suspension of active principle, relative to the totalweight of said oral veterinary composition.

Without wishing to be bound by any theory, the applicant thinks that, inthe above embodiments, the particles of active principle are, within thecoating layer of fat which comprises them, covered partially orcompletely with a film of oil derived from the initial oily suspension.Said film of oil is of a nature to further reinforce the protection ofthe active principle against possible harmful effects caused by theexternal environment. Moreover, the presence of said oil film on thesurface of the particles of active principle may contribute to thecharacteristics of the pharmacokinetic profile of the oral veterinarycomposition. Finally, the presence of said oil film on the surface ofthe particles of active principle could also produce an effect ofmasking the taste or odor of the active principle with respect to theolfactory or gustatory sensitivity of the animals and thus reinforce theproperties of palatability of the oral veterinary composition of theinvention.

Moreover, in a composition according to the invention, the activeprinciple is included in a nutritional composition so that saidcomposition has a long residence time in the stomach. With a compositionaccording to the invention, gastric emptying is substantially delayed incomparison with the gastric emptying observed on ingestion of apharmaceutical formulation, including a delayed-release pharmaceuticalformulation. In consequence, inclusion of the active principle in themass of a composition comprising a core of complete feed extrudatecontributes substantially to obtaining a pharmacokinetic profile that isparticularly suitable for the active principles whose target sites arelocated in the small intestine, such as the angiotensin-convertingenzyme inhibitors such as benazepril. As an illustration, it is knownthat the gastric residence time of a dry food, for example pellets, inthe gastric cavity of a cat is about 14 hours to 16 hours. Bydefinition, an identical gastric residence time is expected with anutritional and medicinal oral composition according to the inventionthat allows release of the whole of the active principle containedinitially in this composition in the stomach before gastric emptyingoccurs, and thus ensure optimal bioavailability of the active principlefor the target sites. These characteristics of a nutritional andmedicinal composition according to the invention are quite particularlyadvantageous for the active principles whose pharmacological effect issubstantially increased on saturation of the target sites by theseactive principles.

In the embodiments of the oral veterinary composition of the inventionin which the active principle is incorporated in the form of waxygranules, the layer of fat comprising the active principle may comprisefrom 0.05 to 2 wt % of the wax, relative to the total weight of saidoral veterinary composition.

Advantageously, the weight ratio of the coating layer of fat to themedicinal agent will be between 1/5 and 1/10, preferably about 1/7.

In these embodiments, the applicant thinks that the layer of wax coatingthe particles of active principle has the functions described above forthe oil film.

Premix or Preconditioning Composition in the Form of an Oily Suspensionof Active Principle

As is disclosed in the present description, a preferred first startingform of an active principle, or preferred premix composition, used formaking an oral veterinary composition according to the invention, is anoily suspension of said active principle. This is a particularembodiment of a medicinal agent according to the invention.

For the oily suspension, an oil is used whose melting point is below 10°C., which includes the oils whose melting point is below 9° C., 8° C.,7° C., 6° C., 5° C., 4° C., 3° C., 2° C., 1° C. or 0° C. In general, anoil is used whose melting point is above −10° C.

The oil constituting the oily suspension may comprise, or consist of, atriglyceride or a mixture of triglycerides, or a polyol ester.

It is possible for example to use a triglyceride of capric acid and/orof caprylic acid, which is notably marketed under the name Miglyol® 810or Miglyol® 812 by the company Sasol (Germany).

It is also possible to use triglycerides of capric acid/capricacid/linoleic acid, which are notably marketed under the name Miglyol®818 by the company Sasol (Germany).

It is also possible to use triglycerides of caprylic acid/capricacid/succinic acid, which are notably marketed under the name Miglyol®829 by the company Sasol (Germany).

It is also possible to use an oil of the propylene glycoldicaprylate/dicaprate type, which is notably marketed under the nameMiglyol® 840 by the company Sasol (Germany).

The oily suspension comprises at least one active principle,advantageously at a rate from 0.1 to 10 wt %, for example from 0.5 to 5wt %, for example about 1 wt %, relative to the total weight of saidoily suspension.

The oily suspension of active principle may also comprise one or morefillers intended to control the density of said suspension so as toallow homogeneous distribution of the particles of active principlethroughout the volume of the suspension, and so as to avoid, or at thevery least greatly reduce, sedimentation of the particles of the activeprinciple. The viscosity adjuster, when it is present in the oilysuspension, advantageously represents from 0.5 to 3 wt %, better stillfrom 1 to 2 wt %, and even better about 1.0 wt %, relative to the totalweight of said oily suspension. As an illustration, the viscosityadjuster may be colloidal silica, for example Aerosil® 200 (EvonikIndustries).

The oily suspension of active principle may also comprise at least onesurfactant, which can improve resuspension. The surfactant, when it ispresent in the oily suspension, advantageously represents from 0.1 to3.0 wt %, better still from 1 to 2 wt %, and even better about 1.5 wt %,relative to the total weight of said oily suspension. For example, anonionic surfactant may be used, such as Tween® 80 (Sigma Chemical).

Thus, the present invention also relates to a premix composition, inparticular for making a nutritional and medicinal composition forveterinary use, comprising an oily suspension of particles of activeprinciple, for example an oily suspension of benazepril, which is notmicroencapsulated.

Premix or Preconditioning Composition in the Form of Hydrophobic Medium,Notably a Wax, in which the Active Principle is Incorporated

As is disclosed in the present description, a preferred second initialform of an active principle, or preferred premix composition, used formaking an oral veterinary composition according to the invention,consists of a hydrophobic wax in which particles of active principle areincorporated. This is another particular embodiment of a medicinal agentaccording to the invention.

A hydrophobic medium of this kind is preferably obtained by techniquesof waxy granulation, which are familiar to a person skilled in the art.

Waxy granulation of the particles of active principle may be carried outin an air-fluidized bed, by kneading or by mixing.

The step of waxy granulation may be carried out by spraying a solutioncomprising at least one waxy compound and a solvent.

In certain embodiments, the solution comprising the waxy compound andthe solvent may also include at least one viscosity adjuster.

The coating solvents are those used conventionally by a person skilledin the art. We may mention as examples water, methylene chloride,ethanol, isopropanol and mixtures thereof.

This process is carried out in an air-fluidized bed, by kneading, bymixing or by any other similar industrial process known by a personskilled in the art.

The drying operation may be carried out in an air-fluidized bed, in arotary dryer under vacuum or by any equivalent technique for removingthe residual solvents.

The waxy compounds used may notably be selected from the groupconsisting of: waxes, Novata waxes, Gélucires (Gattefossé) andSuppocires (Gattefossé), glyceric macrogols, fatty acids (of the stearicacid type), esters of fatty acids, glycerol monostearate, Précirols(Gattefossé), Compritols (Gattefossé).

Among these waxy compounds, advantageously the hydrophobic waxycompounds will be used, and even more advantageously hydrophobic waxycompounds having a low HLB (hydrophilic-lipophilic balance) and having amelting point between 35 and 53° C., preferably between 37 and 43° C. Wemay mention, nonexhaustively, the waxy compounds marketed under thenames Gélucires 43/01 and NovataAB.

These waxy compounds may be combined with glycerol monostearate (GMS).

Hydrophobic waxy compounds may be used that have a low HLB(hydrophilic-lipophilic balance) and have a melting point between 35° C.and 53° C., preferably between 37° C. and 43° C. in the presence oflubricants. We may mention, nonexhaustively, Gélucire 43/01 andNovataAB, optionally combined with glycerol monostearate (GMS).

The waxy compound may also be glycerol palmitostearate, for examplePrecirol® AT05 (Gattefossé).

The starting solution also advantageously comprises a filler, such as asugar, or a sugar derivative such as mannitol or xylitol.

In the paste end product, the active principle advantageously representsfrom 0.1 to 10 wt %, better still from 0.5 to 5 wt %, for example about1 wt %, relative to the total weight of the wax composition containingthe latter.

Advantageously, the waxy compound(s) are present in an amount rangingfrom 10 to 50 wt %, better still from 15 to 40 wt %, for example from 20to 30 wt %, which comprises about 25 wt %, relative to the total weightof the wax composition containing the latter.

In the wax composition, the filler(s) may be present in a significantamount, for example at a rate of more than 50 wt %, even up to at least75 wt %, relative to the total weight of said wax composition. Thefiller or fillers, when present, represent less than 80 wt %, relativeto the total weight of the wax composition containing the latter.

Thus, the present invention also relates to a premix composition, inparticular for making a nutritional and medicinal composition forveterinary use, comprising an oily suspension of particles ofnon-microencapsulated benazepril.

The present invention also relates to an oral composition as defined inthe present description, for use as a medicinal product for veterinaryuse.

The invention also relates to an oral composition as defined in thepresent description, for use for preventing or treating a disorder or adisease in an animal, in particular in a companion animal, andespecially a dog or a cat.

The invention notably relates to a composition as defined in the presentdescription for use for preventing or treating renal insufficiency in anonhuman mammal.

The invention also relates to the use of a composition as defined in thepresent description, for making a nutraceutical for preventing ortreating renal insufficiency in a nonhuman mammal.

The present invention also relates to a method for preventing ortreating a disorder or a disease in an animal, comprising a step inwhich a suitable amount of an oral veterinary composition as defined inthe present description is administered to said animal, preferably bythe oral route.

The present invention is further illustrated by the examples givenbelow.

EXAMPLES Example 1: Preparation of an Oral Veterinary Composition with aPreconditioned Active Principle in the Form of an Oily Suspension

1.1. Preparation of the Medicated Premix in the Form of Oily Suspension:

The active principle is benazepril hydrochloride in the form of a powderhaving an average particle size from 10 to 35 μm marketed by the companyAurobindo (India).

An oily suspension based on Miglyol®840 (Condea GmbH, Germany) isprepared, to which Aerosil®200 (colloidal silica—2% w/w) and Tween®80(ester of polyethylene and sorbitol—0.5% w/w) are added.

The powder of active principle is added to the above oily suspension andthe oily suspension is obtained by homogenizing by stirring using astirrer of the Rotor Stator type until a homogeneous suspension isobtained. The final concentration of the active principle in the oilysuspension was 1.0 wt %, relative to the total weight of the oilysuspension.

1.2. Preparation of the Oral Veterinary Composition

A single-component complete feed extrudate of the RenalCat® typemarketed by the company Virbac Nutrition is supplied in the form ofpellets that have been treated by hot spraying of liquid fat (treatedextrudate core).

The treated extrudate cores are coated by kneading in a paddle mixer ofthe kneader type, in the following operating conditions: introduction ofthe treated extrudate cores, introduction of the medicated premixprepared as described in § 1.1. above, and introduction of a mass ofhydrophobic material, preferably duck fat, lard or fish oil, in a weightratio of medicated premix/hydrophobic material of 1/7, mixing for max.300 seconds.

In each pellet of the final composition, the hydrophobic layercontaining the active principle represents about 12 wt %, relative tothe total weight of the pellet.

Example 2: Preparation of an Oral Veterinary Composition with aPreconditioned Active Principle by Incorporation in a Wax

2.1. Preparation of the Preconditioned Active Principle in the Form ofWaxy Granules

The active principle is benazepril hydrochloride in the form of a powderhaving an average particle size from 15 to 30 μm marketed by the companyAurobindo (India).

Waxy granules of the active principle are prepared by dry granulationwith a mixture of Precirol® ATO 5 (glycerol distearate) and Pearlitol®160C (mannitol), at a rate of 1% (weight/weight) of benazeprilhydrochloride, 25% (weight/weight) of Precirol® and 74% (weight/weight)of Pearlitol® in a granulator of the Rotolab type with double-jacketheating equipped with tools for mixing (impeller) and for breaking uplumps (chopper), in the following operating conditions: temperaturesetting 50 to 80° C., product temperature 50 to 70° C., stirring speedbetween 100 and 1000 rpm.

2.2. Preparation of the Oral Veterinary Composition

A complete feed extrudate of the Renal Cat® type marketed by the companyVirbac Nutrition is supplied in the form of pellets that have beentreated by hot spraying of liquid fat (treated extrudate core).

The pellets of treated extrudate are coated by kneading in a paddlemixer of the kneader type, in the following operating conditions:introduction of the treated extrudate cores, introduction of themedicated premix prepared as described in § 2.1. above, and introductionof a mass of hydrophobic material, preferably duck fat, lard or fishoil, in a weight ratio medicated premix/hydrophobic material of 1/7,mixing for max. 300 seconds.

The extrudates and the duck fat are introduced, mixed for 20 seconds andthen the medicated premix is introduced (and other components such asvitamins), mixing for 90 seconds.

In each pellet of the final composition, the hydrophobic layercontaining the active principle represents between about 4.77 wt %(first variant above) and 9.59 wt % (second variant above), relative tothe total weight of the pellet.

Example 3: Stability of the Oral Veterinary Composition

In this example, the properties of stability of the oral veterinarycompositions as described in examples 1 and 2 were evaluated.

A. Materials and Methods

Pellets of each of the oral veterinary compositions described in example1 or in example 2 are stored in sealed three-ply bags (PE, OPP, AL).

The bags containing the pellets are placed in several chambers withcontrolled temperature and level of relative humidity (RH).

The storage conditions were as follows: (i) 5° C.; (ii) 25° C., 60% RH;(iii) 30° C., 65% RH and (iv) 40° C., 75% RH.

The stability of the active principle contained in the pellets wasevaluated after different storage times in the conditions stated above.The stability of the active principle was evaluated by measurement byHPLC (high-performance liquid chromatography).

Operating Conditions

Medicated Premix (Medicinal Agent)

Column: Uptishère ODB (Length (cm): 25, ID (mm): 4.60, Grafting: C18,Granulometry (μm): 5, T° C. column furnace: 25° C., Flow: 0.8 ml/min,Injection: 20 μl, UV detection: 240 nm, Mobile phase: KH₂PO₄ 5 g/L(30%): Methanol (70%) Solvent for dilution: MeOH/H₂O (70/30).

Preparation of the Solutions

Analysis solution of the premix according to example 1: The product isextracted with isooctane/MeOH/H₂O mixture and microfiltered, thedilution is adjusted and then the product is injected into the column.

Analysis solution of the premix according to example 2: The product isextracted in ethanol, made up with water and microfiltered, the dilutionis adjusted and then the product is injected into the column.

Medicated Feed:

Column: Uptishère ODB (Length (cm): 25, ID (mm): 4.60, Grafting: C18,Granulometry (μm): 5, T° C. column furnace: 25° C., Flow: 0.8 ml/min,Injection: 40 μl, UV detection: 240 nm, Mobile phase: KH₂PO₄ 5 g/L(30%): Methanol (70%) Solvent for dilution: MeOH/H₂O (70/30).

The product is extracted with pure methanol, the dilution is adjustedand then the product is injected into the column.

TABLE 1 Stability of the medicated premix suspension I 1.5 months 3months 6 months 12 months  5° C. 99.6 100 99.8 98.8 25° C./60% RH 99.099.9 98.4 97.0 30° C./65% RH 98.5 99.0 98.3 96.8 40° C./75% RH 100 99.499.2 —

TABLE 2 Stability of the medicated feed made from I 1.5 6 months 3months months 9 months 12 months  5° C. 102.3 98.3 95.9 98.4 102 25°C./60% RH — — 100.1 93.2 — 30° C./65% RH — — 93.3 87.8 90.6 40° C./75%RH 86.0 92.4 74.7 — —

TABLE 3 Stability of the medicated premix waxy granules II 1.5 months 3months 6 months 25° C./60% RH 100.7 100. 98.9 40° C./75% RH 97.9 97.592.7

TABLE 4 Stability of the medicated feed made from II 1.5 3 6 9 12 18 24months months months months months months months 25° C./ 99.5 92.2 99.292.4 96.7 95.1 85.8 60% RH 40° C./ 87.6 78.9 72.1 — — — 75% RHB. Results

The results obtained showed that:

-   -   for the medicated premix according to example 1, the content of        active principle is 99.2% after storage for 6 months at 40° C.        and 75% relative humidity and is 96.8% after storage for 12        months at 30° C. and 65% relative humidity;    -   for the medicated premix according to example 2, the content of        active principle is 98.9% after storage for 6 months at 30° C.        and 65% relative humidity and is 92.7% after storage for 6        months at 40° C. and 75% relative humidity;    -   for the oral veterinary composition according to example 1, the        content of active principle is 98.4% after storage for 9 months        at 4° C. and is 93.2% after storage for 9 months at 25° C. and        60% relative humidity;    -   for the oral veterinary composition according to example 2, the        content of active principle is 94.9% after storage for 18 months        at 25° C. and 60% relative humidity.

The results show that the specific characteristics of an oral veterinarycomposition of the invention allow a high level of stability in storage,although the particles of active principle are not coated with aprotective layer against moisture, and are not micro-encapsulated, whichruns counter to what a person skilled in the art expects, who believesthat encapsulation is indispensable for preservation of the activeprinciple.

Example 4: Palatability Properties of the Oral Veterinary Composition

In this example, the palatability properties of oral veterinarycompositions obtained according to the details in examples 1 and 2 wereevaluated.

A. Materials and Methods

A.1. Test system

A.1.1 Characterization

The characteristics of the cats are given below.

Breed: European

Number: 21

Sex: 10 female and 11 male

Age: average 2.9 years; min.: 1.5 months-max.: 5.8 years

Weight: 3.88 kg; min.: 2.28 kg-max.: 5.45 kg

Identification: An identification card was placed on the doors of theboxes housing the animals showing the code of the study, the identifyingnumber, breed, sex and date of birth of the cat.

The animals were in good health at the time of inclusion and had notreceived treatment in the 15 days preceding the start of the study.

A.1.2 Conditions for housing and maintenance

The animals remained in their usual housing locations. Maintenance wascarried out every day except Sunday. The environmental parameters wererecorded every day. A photoperiod of 12 h of light and 12 h of darknesswas maintained. Food was distributed every day except Sunday. Being acriterion of the study, the distribution and withdrawal of food arepresented in the paragraph “A.3.2 Administration conditions”. Water wasavailable ad libitum.

A.1.3 Constitution of the Groups and Acclimatization

During the test week, the animals were fed individually in the morninguntil about 16 h. So that they should become accustomed to these housingconditions, they were placed in individual cages in the same conditionsin the first study week.

A.2. Treatments

The products were distributed randomly. On the first test day, each catis placed in a kennel in the morning between 7 h and 9 h. The food, 80 gof test product, was offered to the animal. The behavior of the cat wasobserved and was reported on the observation cards. The food bowls wereremoved between 12 h and 14 h and the amounts of pellets that remainedwere weighed.

Test Products:

A: reference food, Renal Cat®

B: medicated feed with waxy granules

C: medicated feed with suspension, batch 1

D: medicated feed with suspension, batch 2

A.3. Test procedure

A.3.1 Experimental plan

The study took place over 4 weeks. On the first day, each cat is placedin an individual cage between 7 h and 9 h. The food, 80 g of testproduct, was offered to the animal. The behavior of the cat was observedand reported on the observation cards. The food bowls were removedbetween 14 h 30 and 16 h 30 and the amounts of pellets that remainedwere weighed.

A.3.2. Administration conditions

In the first week, all the animals were fed with Renal Cat® food(marketed by the company Virbac Nutrition).

Then, for the subsequent weeks, on Monday the animals were all fed withthe reference food, in the morning.

On Tuesday to Friday, the cats received 4 consecutive days of randomizedadministration of each of the test products, including the referencefood.

From the first to the last test day, the person distributing the pelletsapplied the following scheme:

Distribution:

1: Weigh 80 g of pellets in a pot, note the exact amount in the “animalfeeding” notebook.

2: Distribute the food bowl with the pellets to the cat

3: Observe the animal during distribution and complete the observationcard

Withdrawal:

Between 14 h30 and 15 h30, weigh the food bowl (food bowls+remainingpellets) and record this in the “animal feeding” notebook

A.3.3 Clinical signs

Clinical observation was carried out during distribution and withdrawalof the food bowls. If an animal required treatment not envisaged in thecontext of this study, the study director (veterinarian) agreed with theorderer on the treatment to be undertaken. However, if a prolonged delaywould have caused the animal unacceptable suffering, the study directorcould administer the appropriate treatment, the orderer being informedof this as soon as possible. None of the animals in the study requiredany treatment beyond those envisaged.

B. Results

B.1 Food Consumption

The first week of administration of Renal Cat® is regarded as the weekof acclimatization of the animals to the food and to the housingconditions. The results obtained during this week are not used for therest of the calculations.

The average amounts ingested per food are presented in Table 5 below.

TABLE 5 Food A B C D Amount (g) 50 50 48 50B.2. Conclusion

Twenty-one cats were fed for 4 weeks with an oral veterinary compositionaccording to example 1 or example 2 or with the reference food RenalCat®. The food was distributed in the morning and removed between 14 h30and 15 h30. The animals were observed every day. For all the formulastested, some clinical signs (vomiting) were recorded without the generalcondition of the animal being affected.

All the feedstuffs demonstrate good palatability, showing thatincorporation of benazepril in the food did not alter the cats' foodintake.

Example 5: Modeling of the Profile of Release of the Active Principle

The pharmacological efficacy of the active principle contained in anoral veterinary composition according to the invention was evaluated,then the results of this evaluation were compared with the level ofpharmacological efficacy of a known pharmaceutical formulationcontaining the same active principle.

The active principle is benazeprilat, derived from the prodrugbenazepril as contained in the oral veterinary compositions described inexample 1.

The profile of the pharmacological effect of the compositions describedin example 1 was compared with the profile of the pharmacological effectof a pharmaceutical formulation of tablets containing granules ofbenazepril coated with a polymer layer, marketed under the nameFortekor®.

A. Materials and Methods

Three experimental groups of six cats were prepared, respectively:

-   -   Group 1: control animals fed with a composition similar to that        described in example 1, but not containing benazepril;    -   Group 2: the oral veterinary composition described in example 1        containing benazepril, and    -   Group 3: the known reference composition Fortekor® The cats in        Group 2 were fed with the oral veterinary composition described        in example 1 and ingested a daily amount of benazeprilat of        about 600 μg/kg.

The cats in Group 3 ingested tablets of Fortekor® at a rate of a dailydose of benazeprilat of 600 μg/kg. The cats were fed immediately afteringesting the tablets containing benazepril HCl.

The treatment of the cats in each of the three groups was carried outfor eight consecutive days.

Blood samples were taken regularly from each cat in each of the threegroups throughout the test. For each blood sample collected, the amountof benazeprilat was measured by tandem mode mass spectrometry(LC-MS/MS). For each blood sample collected, the activity of theangiotensin-converting enzyme (ACE) was measured. The percentageinhibition of ACE was calculated using the blood level of ACE activityof the cats in Group 1 as reference (0% inhibition).

A PK/PD analysis based on the physiological model described by Toutainet al. (2000) was performed for estimating the pharmacokinetics (PK) andpharmacodynamics (PD) of the two groups tested.

The profiles of the pharmacological effect (percentage inhibition of theangiotensin-converting enzyme (ACE) as a function of time) weredetermined for the various compositions using the model described byKing et al. (2003, J Vet Pharmacol Ther, Vol. 26(3): 213-224), asdescribed below.

B. Results

Predictive curves were obtained by modeling and are shown in FIGS. 1 and2.

The results in FIG. 1 show that the pharmacokinetic profile and thepharmacological effect (% ACE inhibition) obtained with the oralveterinary composition are very different from those obtained with thecomposition Fortekor®. A “delay effect” can be seen for the Inv group(time difference in hours of the dotted curves relative to the Fortekor®group).

FIG. 2 illustrates comparison of the curves of ACE inhibition,respectively (i) with the oral veterinary composition described inexample 1 “Inv” (continuous line) and (ii) with the Fortekor®composition (discontinuous line).

The results in FIG. 2 show that the composition Inv (overall average of75.14% ACE inhibition) is substantially more effective than theFortekor® reference composition (overall average of 59.62% ACEinhibition).

Example 6: Comparative Study of the Pharmacokinetic Profiles of aComposition According to the Invention (Inv) and of the CommercialComposition Fortekor®

A comparative study of the pharmacokinetic data (i) of an oralveterinary composition prepared as stated in example 1 (“Inv”) and (ii)of the commercial composition Fortekor® was carried out.

The pharmacokinetic data were analyzed with the software Kinetica 5.0.

Summary of the Characteristics of the Study:

Reference: Fortekor 2.5 mg tablet (benazepril hydrochloride).

Test: Inv 50 mg benazepril hydrochloride/kg (of food), adm about 0.67 mgof hydrochloride benazepril/kg 12 cats, European male (3.7 to 4.5 kg,3.1 to 6.4 years).

Oral administration for 8 days

2 groups in parallel (2×6 cats)

The food ration is fixed at 70 g of Renal Cat® alone or 50 g Inv+20 gRenal Cat®

-   -   Fortekor+(70 g) Renal Cat® (specific meal)    -   Inv (50 g)+(if everything was consumed) Renal Cat® (20 g)        Monitoring of food consumption (2 h after administration of the        meal for Fortekor and 0.5, 2 and 6 h for Inv)

Collection of blood: T0 on D−1

-   -   D1 then at 2, 6, 8, 12 h after administration    -   D2, D3, D4, D5, D6, D7 and D8 before administration in the        morning    -   D4 then at 2, 6, 8, 12 h after administration    -   D8 then at 2, 6, 8, 12 h, 24 h (D9) and 48 h (D10)        Method of analysis: LC/MS-MS, LOQ: 0.5 ng/mL for benazepril and        benazeprilat        Monitoring of the Food Intake of the Cats in the Experiment Over        8 Successive Meals (D1 to D8) at 2 h (Fortekor Group) or 30 Min,        2 h, 6 h and 24 h (Inv Group) after Distribution of the Meal

The results are presented in Table 6 below:

Food monitoring was carried out 30 min, 2 h, 6 h and 24 h afterdistribution of the meal for all the cats.

This table emphasizes the very good palatability of the productaccording to the invention.

TABLE 6 Status Food Subject Food intake after 2 h for the 8predominantly Food intake intake on No. Status days observed on D1 D8 1Group 1 - Fortekor ® 7 × all consumed in 2 h VF and/or F VF and/or F Sor VS 1 × remainder 22 g after 2 h 2 Group 1 - Fortekor ® 6 × allconsumed in 2 h VF and/or F S S or VS 2 × remainder 3 & 15 g after 2 h 3Group 1 - Fortekor ® 8 × all consumed in 2 h VF and/or F VF or F VF or F4 Group 1 - Fortekor ® 8 × all consumed in 2 h VF and/or F VF or F VF orF 5 Group 1 - Fortekor ® 5 × all consumed in 2 h * VF and/or F S or VS Sor VS 3 × remainder 15, 14 & 20 g after 2 h 6 Group 1 - Fortekor ® 3 ×all consumed in 2 h * Tendency to be S S or VS VF or F 5 × remainder 42,40, 21, 18, or VS & 17 g after 2 h 7 Group 2 - Inv 8 × all consumed in0.5 h VF VF VF 8 Group 2 - Inv 2 × all consumed in 0.5 h F and VF VF F 6× all consumed in 2 h 9 Group 2 - Inv 8 × all consumed in 0.5 h VF VF VF10 Group 2 - Inv 3 × all consumed in 6 h VS and S VS S 5 × all consumedin 24 h 11 Group 2 - Inv 8 × all consumed in 0.5 h VF VF VF 12 Group 2 -Inv 5 × all consumed in 2 h F and S S F 3 × all consumed in 6 hVF very fast, F fast, S slow, VS very slow.Table 6Plasma Concentrations of Benazepril:

TABLE 7 Concentration of Time since benazepril (ng/ml) treatmentFortekor Inv Day 1 T0 Nd Nd T2h 8.48 ± 10.50 5.19 ± 2.55 T6h Nd 4.27 ±2.21 T8h Nd 3.48 ± 2.29 T12h Nd 3.02 ± 1.58 Day 2 T0 Nd Nd Day 3 T0 NdNd Day 4 T0 Nd Nd T2h 8.08 ± 5.06 4.54 ± 2.28 T6h Nd 5.35 ± 3.10 T8h Nd4.07 ± 3.00 T12h Nd 3.37 ± 1.75 Day 5 T0 Nd Nd Day 6 T0 Nd Nd Day 7 T0Nd Nd Day 8 T0 Nd Nd T2h 7.21 ± 2.56 5.21 ± 2.17 T6h  3.5 ± 3.43 4.79 ±2.14 T8h 2.42 ± 2.75 3.55 ± 1.79 T12h 1.62 ± 1.77  3.1 ± 1.76 T24h Nd NdT48h Nd Nd

Lower benazepril concentrations are observed with Inv relative toFortekor®, but they are maintained for 8 to 12 h.

Comparison of the PK/PD Parameters

TABLE 8 PK parameters D1 D4 D8 Cmax (ng/mL) Fortekor 7.67 ± 9.61 7.32 ±4.89 7.21 ± 2.56 Inv 5.44 ± 2.27 5.80 ± 2.94 5.49 ± 2.16 Tmax (h)Fortekor 2.00 ± 0.02 2.02 ± 0.02 2.00 ± 0.00 Inv 3.34 ± 2.06 4.67 ± 2.064.00 ± 2.19 AUClast (ng · h/mL) Fortekor 8.72 ± 9.33 10.79 ± 13.09 39.98± 31.09 Inv 45.80 ± 20.41 48.21 ± 26.78 46.78 ± 19.66

Cmax is higher and more variable in group 1 (Fortekor®) than in group 2(Inv) and Tmax is lower in group 1 (Fortekor) than in group 2 (Inv).Benazepril exposure is higher after administration of Inv.

Results for Plasma Concentration of Benazeprilat

Pharmacokinetic parameters of benazeprilat on D1, D4 and D8 for groups 1(Fortekor®) and 2 (Inv):

TABLE 9 day of analysis Ratio of PK parameter D1 D4 D8 accumulation Cmax(ng/mL) Cmax 1 (n = 5) Cmax ss =Cmax ss/Cmax 1 Fortekor ® 57.16 ± 22.6943.64 ± 9.51 54.80 ± 27.03 1.02 ± 0.49 Inv 15.72 ± 3.78  20.08 ± 3.4222.23 ± 2.82  1.47 ± 0.35 Cmin (ng/mL) Cmin 1 Cmin ss =Cmin ss/Cmin 1Fortekor ® 2.55 ± 1.31 2.88 ± 0.92 1.20 ± 0.22 Inv 4.57 ± 1.49 8.65 ±3.25 2.02 ± 0.82 Tmax (h) Fortekor ® 2.00 ± 0.02  2.02 ± 0.02 2.00 ±0.00 Inv 13.35 ± 5.49   9.66 ± 2.65 7.38 ± 3.29 AUClast (ng · h/mL)Fortekor 279.89 ± 107.70 270.23 ± 76.85 476.28 ± 172.44 1.44 Inv 242.11± 48.23  356.79 ± 46.93 504.48 ± 111.70 1.55

At steady state, Cmax was 2 times higher in the Fortekor® group relativeto the Inv group.

TABLE 10 Pharmacokinetic parameters (LC/MS-MS, LOQ 0.5 ng/mL) AUClast(ng · h/mL) D1 D4 D8 Fortekor ® 279.89 ± 107.70 270.23 ± 76.85 476.28 ±172.44 Inv 242.11 ± 48.23  356.79 ± 46.93 504.48 ± 111.70

The mean pharmacokinetic profiles of benazeprilat are shown in FIG. 6.

The kinetic profiles of the mean benazeprilat concentrations aredifferent after administration of Fortekor® and after administration ofInv. The mean Cmax values for benazeprilat are lower, whatever day isconsidered, in the group treated with Inv relative to the group treatedwith Fortekor®.

The benazeprilat concentrations measured before each administration ofthe tablet, between D2 and D8, are higher after administration of Invthan after administration of Fortekor®. Better maintenance of theminimum benazeprilat concentrations is observed in group 2 (Inv)relative to group 1 (Fortekor®).

Results and Conclusions of the Test

The two products, Fortekor® and Inv, are in two different forms: atablet and a medicated feed.

The average doses administered of the form of Fortekor and of Inv areapprox. 600 μg/kg and approx. 510 μg/kg (mean values on D1). The doseadministered in the form of Fortekor is therefore higher than the doseadministered in the form of Inv.

Observations Concerning the Profiles

The results are illustrated notably in FIGS. 3, 4, 5 and 6.

There are two different formulations having two different profiles:

-   -   Administration of benazepril by the oral route (Fortekor®) in        the form of a tablet produces a profile of the “adm bolus” type        with a peak at 2 h (Tmax) reaching a maximum concentration        (Cmax) fluctuating between 30 and 190 ng/mL followed by a        decrease in the plasma concentrations (see FIG. 3). Therefore        rapid and pronounced availability of benazeprilat is observed in        the plasma but short persistence over time.    -   Administration of benazepril by the oral route (Inv) in the form        of a medicated feed produces a profile of the “adm        perfusion/delayed” type with an increase in the concentration        over time, reaching a plateau (Tmax) between 6 and 12 h with a        maximum concentration (Cmax) fluctuating between 10 and 71 ng/mL        followed by a slow decrease in the plasma concentrations (see        FIG. 4). Therefore slower and less pronounced availability of        benazeprilat is observed in the plasma, with longer and constant        persistence over time.

The forms of administration have a significant influence on the plasmaprofile of benazeprilat in the cat.

After observation of the pharmacokinetic data, and taking into accountthe dose actually administered, administration of benazepril in the formof medicated feed (Inv) always leads to an AUC last and to an AUC lastcorr of benazeprilat greater than those produced followingadministration of benazepril in the form of a tablet (Fortekor®), as isillustrated in FIGS. 4 and 5 respectively. We may therefore concludefrom this that administration of the product according to the inventionis at least as effective as the reference treatment, while offering aproduct that is very easy to administer and therefore allowing excellentcompliance with the treatment. In addition, it should be pointed outthat in this test, 100% of the cats took the Fortekor tablet, by gavage,provided by veterinarians accustomed to this procedure whereas inpractice, in contrast, in the home of the cat's owner, effectiveingestion of the tablet will be much more random, depending on the catand the dexterity of the owner, making the results of product exposureeven poorer for Fortekor than for the product according to theinvention.

The invention claimed is:
 1. A nutritional and medicinal oralcomposition for veterinary use comprising a core of complete feedextrudate coated with at least one layer of fat, said layer of fatcomprising at least one medicinal agent, said medicinal agent comprisingat least one preconditioned active principle in the form ofnon-encapsulated microparticles devoid of a protective outer layer,wherein the at least one preconditioned active principle is in the formof: (i) a solution or a suspension of said active principle in an oilyliquid, or (ii) waxy granules.
 2. The composition of claim 1, whereinthe active principle is at least one selected from the group consistingof an angiotensin-converting enzyme inhibitor (ACE inhibitor), a renininhibitor, an angiotensin II receptor antagonist, firocoxib,ciclosporin, S-adenosyl-methionine, eplerenone, spironolactone,amlodipine, and levosimendan.
 3. The composition of claim 2, wherein theangiotensin-converting enzyme inhibitor is at least one selected fromthe group consisting of benazepril, enalapril, ramipril, quinapril,preindopril, lisinopril, imidapril, zofnopril, trandolapril, and saltsthereof.
 4. The composition of claim 2, wherein the renin inhibitor isat least one selected from the group consisting of pepstatin, a peptideanalog of pepstatin, a peptide mimetic of pepstatin, and a non-peptidemimetic of pepstatin, and salts thereof.
 5. The composition of claim 2,wherein the angiotensin II receptor antagonist is at least one selectedfrom the group consisting of valsartan, telmisartan, losartan,irbesartan, azilsartan, omesartan, and salts thereof.
 6. The compositionof claim 1, wherein the active principle is benazepril or a saltthereof, in particulate form.